Tablets are pictured on the production line of Bristol Myers Squibb's pharmaceutical plant in Agen, southwestern France, on March 29, 2018. ( GEORGES GOBET/AFP/Getty Images)
The casino didn’t always call out to Denise Miley.
At most, she and her husband, Brad, would drive over to the Mystic Lake Casino Hotel, just outside Minneapolis, a few times a year.
Then, in the fall of 2014, she got an itch to go more often. She’d ride her bike the 35 miles down to the casino and ask her husband to pick her up. It was just exercise, she’d tell him. Sometimes she would start driving to the office where she worked as an accountant. But when the freeway split off, she’d peel south and head to the slots.
“I didn’t have a word for it back then, but I was starting to feel compulsed,” she said. “I wanted to stay longer, and longer, and longer.”
She also had no idea her compulsion might be linked to a drug she began taking for depression and anxiety a few weeks before she began seriously gambling. By the time she stopped taking aripiprazole — an antipsychotic sold under the brand name Abilify — she’d stayed in the casino long enough to lose more than $150,000.
Miley, 41, filed a lawsuit in January 2016 against the drug makers Bristol-Myers Squibb and Otsuka, alleging the drug — one of the best-selling in the world — caused compulsive behavior. The suit contends that the companies knew or should have known it could create such urges, and didn’t adequately warn the thousands of people in the U.S. who use the medication each year.
Hundreds more people have since sued the companies, claiming that the drug caused them to gamble, eat, or have sex compulsively. And the Food and Drug Administration signaled its own concern in a 2016 safety warning, saying that uncontrollable urges to gamble, binge eat, shop, and have sex had been reported with use of the antipsychotic.
“We have people who have lost their retirement accounts, spent their children’s college funds, blown through a lifetime of savings,” said Gary Wilson, an attorney with Robins Kaplan, a firm representing some of the plaintiffs, including Miley.
Scientists haven’t figured out how, exactly, a drug might trigger compulsive behavior. Psychiatrists say that even if Abilify does have a role, it’s probably just part of the explanation, since millions of people take the drug without experiencing such problems.
Otsuka, which developed the drug, and Bristol-Myers Squibb, which marketed it jointly with Otsuka in the U.S., have denied the allegations. Bristol-Myers Squibb referred questions about Abilify to Otsuka, which said it could not comment on pending litigation.
The lawsuits have all been lumped together, and the case is presided over by Judge M. Casey Rodgers in the Northern District Court of Florida. The judge picked three bellwether lawsuits to go to trial in a bid to spur a resolution for the other cases, but those three were settled out of court earlier this year for an undisclosed amount.
Now, Rodgers has ordered the thousands of other plaintiffs and the drug makers to work out a framework for a global settlement by Sept. 1. At the same time, the court is working to pick a new group of cases to move to trial if a settlement can’t be reached.
Blockbuster Drug Spurs Safety Warning
The lawsuits are the latest chapter in the roller-coaster history of Abilify. It was approved by the FDA for schizophrenia in 2002. It’s since been approved for treating bipolar disorder, irritability associated with autistic disorder, Tourette’s syndrome, and major depressive disorder.
In 2007, Bristol-Myers Squibb agreed to pay more than $500 million to settle federal charges that it illegally marketed the drug to pediatric physicians and nursing homes. And in 2016, the company reached a $19.5 million settlement with 42 states and Washington, D.C., which accused the drug maker of illegally promoting Abilify to people with Alzheimer’s disease and other forms of dementia.
But it hasn’t all been bad news. Aripiprazole remains one of the most-prescribed drugs on the market. And though it went generic in the U.S. in 2015, it continues to generate big sales. The brand-name version of the drug has raked in more than $51 billion worldwide since it was approved, according to IQVIA, a health care analytics company.
And in 2017, the FDA approved Abilify MyCite, a version of the drug embedded with a sensor that can alert a patient’s physician or caregiver when its been ingested. It was the first approval of a so-called smart pill.
As the drug grew increasingly popular, reports kept cropping up that a small number of patients taking the drug had started gambling uncontrollably and experiencing other compulsive behaviors. Between November 2002 and May 2016 when the FDA issued its warning, there were 184 case reports linking the drug to impulse control problems in the medical literature and the FDA’s adverse event database, according to the agency.
The European Medicines Agency was the first regulator to issue a warning, in 2012, that Abilify had been linked to compulsive behavior. In 2015, Canadian drug regulators followed suit. Both required the drug makers to change the labeling, but “pathological gambling” wasn’t added as a potential adverse event to Abilify’s labeling information until January 2016. The FDA didn’t issue a warning to the public until May 2016.
When asked about the reasons for the delay compared with warnings issued in other countries, an FDA spokesperson said, “Our safety signal folks are always reviewing the research.”
Otsuka maintains that there weren’t any signs the drug might be linked to pathological gambling in its initial clinical trials. In one large study — testing Abilify paired with the antidepressant bupropion, the exact combination that Miley was prescribed — the drug makers reported there weren’t any unexpected adverse events.
But Miley said that wasn’t her experience.
The Itch to Gamble Grows
It never occurred to Miley that the drug might be to blame for her growing urge to gamble. She started taking the drug in September 2014, two years before the FDA went public with its warning.
Nor did it raise a red flag for her psychiatrist when Miley mentioned offhand at an appointment that fall that she’d been gambling more. She pitched it almost as a good thing.
“I remember saying, ‘We’re going to the casino a lot more. We’re doing it for an excursion — we’re getting out of the house,’” Miley said.
Miley went back to work, but only part time and with the option to work remotely from her home in Maple Grove, Minn. That meant she could go to the casino without anyone realizing where she’d gone. Some days, she told herself she didn’t have that much work to do. Other days, she just ended up there. Miley’s husband knew she sometimes went to the casino alone — but he had no idea how often. She didn’t always tell him. She hated how she felt: alone and ashamed.
“This whole thing snowballed extremely fast,” she said. Looking back, she felt so distant from herself — a dedicated mom to four kids who calls herself her family’s “rock.”
That fall, if her oldest son’s high school basketball games were anywhere near the casino, she’d dash over during halftime. She told her family she was popping out to do some quick Christmas shopping.
“I had the full intention of going back to his games,” she said. “But I’d sit there and keep gambling and gambling.”
More than once, she didn’t make it back and had to ask someone else to drive her son home. She was losing money, and growing more and more concerned. She finally told her husband she’d lost $10,000.
She grew increasingly desperate to win the money back. “That was the first time I had considered or threatened suicide,” she said.
She found herself in the same brutal spiral that many of the other plaintiffs say they’ve found themselves in: They started taking Abilify to grapple with depression and other serious psychiatric conditions, but then started experiencing compulsions that crushed them with guilt and damaged their relationships — feeding their depression.
Miley’s husband convinced her to talk to a physician who specialized in gambling addiction and who recommended she enter inpatient treatment. But there weren’t any openings. So her husband took her car away, hoping to cut off her ability to get to the casino. She was supposed to take the bus to work.
“That’s what he thought I would do,” she said. She did take the bus to work. Then, she’d wait for the bank to open so she could take money out of their account and hop on the lightrail to the Mall of America, where she caught another bus to the casino. Sometimes she made it back to work, but other times she’d miss the bus. Once, she took a taxi and had it drop her off at the bus station, so it looked like she took the bus home from work.
“It wasn’t me. It just wasn’t me at all during those times,” she said.
That early interaction with her psychiatrist still haunts her. What if he had known about the possible link to Abilify? What if he had taken her off the drug, right then and there? Before the compulsion had stripped her of her savings. Before it had harmed her relationships with her family and friends. Before it had threatened her career. Before it had made her think about suicide.
“I just look back a lot and go, ‘How this could have been different,’” she said. “That’s where I get angry.”
Scientists stumped by a rare link
The science on the potential link between Abilify and impulse control problems is far from settled.
A quick biology lesson: Abilify is a partial dopamine agonist, which means it acts on dopamine, a neurotransmitter that ferries signals between neurons in the brain. It’s involved in multiple pathways, including one that regulates reward processing, pleasure, and motivation.
Both sides battled it out in court over the question of whether Abilify is capable of causing uncontrollable impulses, roping in a slew of experts to testify on either side. In March, Rodgers ruled “there’s a genuine dispute of material fact.” That is, it’s not clear what might be happening, but there isn’t enough evidence to prove it’s impossible.
Experts say the more critical question — and the bigger mystery — is why impulse-control problems might show up in just a small slice of the millions of patients who take Abilify each year.
“If it were as simple as it causing [the behavior], then the streets would be filled with impulsive people,” said Dr. Jon Grant, a psychiatrist who studies impulsive-compulsive disorders at University of Chicago.
Answering that question would take a significant amount of time and money, experts said. It would require a randomized trial and a ton of baseline data from brain scans, blood tests, and detailed patient histories to tease out what factors might be at play.
“If we stick to science, we have to say there’s a very interesting signal there that’s worth investigating,” said Dr. Timothy Fong, a psychiatrist who serves as the co-director of the University of California, Los Angeles, gambling studies program. “But to do that investigation will take a massive amount of resources,” he added.
There’s also a looming question of how responsible the drug might be for impulse control issues in some patients, if at all, Grant said. If it were shown that the drug causes impulse control problems in people with a certain genetic makeup, or people who were exposed to certain environmental factors, what percent of the blame could be placed on the drug?
“The legal system looks at it very differently,” Grant said.
One piece of evidence cited by the plaintiffs: When some patients started taking the drug, they experienced compulsive behavior. When they stopped the drug, it stopped. In some cases, when a patient started taking Abilify again, the impulses reportedly picked right back up where they’d left off. In its 2016 warning, the FDA noted that in the majority of case reports, the compulsions happened in people with no prior history of impulse control problems.
It’s also not the first drug linked to such problems. Similar issues have been seen with certain Parkinson’s drugs that also work on the dopamine system.
“The story [about Abilify] is not a story that’s unusual or surprising,” said Fong.
A promise to get help
One night in February 2015, Miley was supposed to be celebrating a close friend’s 60th birthday. It was the kind of neighborhood get-together she ordinarily gets excited about. But that morning, she took a familiar trip — down to work and on to the casino.
A week earlier, Miley had tried to take $50,000 out of her retirement account, but was told it was going to take several days to get the money. With the casino clawing at her brain, she instead took out a $50,000 loan. She was winning the day of the party — up so much that she thought she’d be able to pay off the debt.
She called her friend and told her she was working late. It was smack in the middle of tax season, so she thought it would be believable.
“I knew I shouldn’t be lying to people,” Miley said. “But the power that I felt like I needed to gamble was so much more than any of that.”
Her friend knew better. Miley was still ahead when the girlfriend showed up with a second friend at the casino at nearly 1 a.m. By that point, Miley had moved to high-stakes poker. One friend told Miley she looked like “a shell of [herself].”
She was embarrassed and distraught. She felt out of control, suicidal. They wanted to drive her to the nearest treatment facility, but Miley wanted to see her kids. So with a promise to return in the morning, they drove her home.
Miley’s husband, meanwhile, had realized she was gone and checked their bank accounts. To his shock, he realized she had been withdrawing their savings. He moved most of their money to an account Miley couldn’t access. When she arrived home, she made him the same promise: “In the morning, we’ll go.”
The next morning, Miley wrote her husband a note saying she was going to work to get everything in order before they went to the treatment facility. She did go to her office. Then she drained the little bit of money her husband had left in their bank account for making their house payment and paying other bills, and made a beeline for the casino.
Her husband was so desperate he considered calling the police, since she’d taken his car. He begged her to come home, and, eventually, Miley agreed. They sped straight toward the treatment facility, more than 100 miles from home.
“Shame. That’s all I felt, this whole time,” Miley recalled. “Shame at what I was putting my family through. Shame at what I was doing. Shame that I couldn’t control this.”
Shortly after she arrived, a provider pulled her off of Abilify and Xanax, which she had been prescribed in December for her growing anxiety, Miley said. She felt the urge to gamble vanish. It happened so fast, in fact, that she felt out of place in treatment.
“I could relate to the [other patients’] feelings of shame and embarrassment,” she said. “But I couldn’t relate to always struggling with wanting to go gambling.”
After 30 days in the inpatient facility, Miley went to a few Gamblers Anonymous meetings and saw a psychologist who specialized in treating gambling addiction, but ultimately stopped going. She just wasn’t experiencing the same urges anymore.
‘I could finally start healing’
In the 3 1/2 years since she stopped taking Abilify, Miley has settled back into a routine. She and her husband love watching their kids play sports and spending time at the lake with her parents and in-laws.
They’re trying to rebuild their lives. While she believes her compulsions were out of her control, that doesn’t change what she went through, or what she put her family through, she said. And it doesn’t return the money she gambled away. She took money out of her retirement account after treatment to pay off the bank loan.
She felt a little bit of the shame lift when the FDA warning came out in 2016. It no longer was just her pointing to Abilify, or even a law firm. Now, federal regulators were saying there might be a link.
“I could finally start healing,” she said. But it still feels raw. She still gets emotional talking about the toll it took on her family.
In late 2016, Miley had to go to the Hard Rock Hotel & Casino in Las Vegas for a work trip. She was absolutely dreading it. It dredged up old feelings that she’d tried to stuff away. She had to walk through the casino floor to get from her hotel room to the meeting rooms.
Not once, Miley said, did she feel like gambling.
This story was originally published by STAT, an online publication of Boston Globe Media that covers health, medicine, and scientific discovery.
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